Synthesis of isohexide ethers and carbonates

ABSTRACT

A facile, straightforward method for alkylation of anhydrosugar alcohols (isohexides) using a carbonate reagent is described. The alkylation method involves: a) contacting in a solution of an isohexide with a dialkyl, diallyl, or diaryl carbonate, and the solution includes a Brønsted base; and b) producing either an alkyl ether or alkyl carbonate of the isohexide compound. The alkylation reaction is in situ, that is, performed without an extrinsic catalyst. According to the method, one can synthesize various ethers and carbonates.

BENEFIT OF PRIORITY

The present application claims benefit of priority of U.S. ProvisionalApplication No. 61/918,795, filed on Dec. 20, 2013, the contents ofwhich are incorporated herein by reference.

FIELD OF INVENTION

The present invention is in the field of art that relates to cyclicbi-functional materials useful as monomers in polymer synthesis and asintermediates generally, and to the methods by which such materials aremade. In particular, the present invention pertains to a method ofpreparing anhydrosugar ethers and carbonates.

BACKGROUND

Traditionally, polymers and commodity chemicals have been prepared frompetroleum-derived feedstock. As petroleum supplies have becomeincreasingly costly and difficult to access, interest and research hasincreased to develop renewable or “green” alternative materials frombiologically-derived sources for chemicals that will serve ascommercially acceptable alternatives to conventional, petroleum-based or-derived counterparts, or for producing the same materials as producedfrom fossil, non-renewable sources.

One of the most abundant kinds of biologically-derived or renewablealternative feedstock for such materials is carbohydrates.Carbohydrates, however, are generally unsuited to current hightemperature industrial processes. Compared to petroleum-based,hydrophobic aliphatic or aromatic feedstocks with a low degree offunctionalization, carbohydrates such as polysaccharides are complex,multi-functionalized hydrophilic materials. As a consequence,researchers have sought to produce biologically-based chemicals that canbe derived from carbohydrates, but which are less highly functionalized,including more stable bi-functional compounds. One class of suchcompounds include anyhydrosugars, such as 1,4:3,6-dianhydrohexitols.

1,4:3,6-Dianhydrohexitols (also referred to herein as isohexides) arederived from renewable resources from cereal-based polysaccharides.Isohexides embody a class of bicyclic furanodiols that derive from thecorresponding reduced sugar alcohols (D-sorbitol, D-mannitol, andD-iditol respectively). Depending on the chirality, three isomers of theisohexides exist, namely: A) isosorbide, B) isomannide, and C) isoidide,respectively; the structures of which are illustrated in Scheme 1.

These molecular entities have received considerable interest and arerecognized as valuable, organic chemical scaffolds for a variety ofreasons. Some beneficial attributes include relative facility of theirpreparation and purification, the inherent economy of the parentfeedstocks used, owing not only to their renewable biomass origins,which affords great potential as surrogates for non-renewablepetrochemicals, but perhaps most significantly the intrinsic chiralbi-functionalities that permit a virtually limitless expansion ofderivatives to be designed and synthesized.

The isohexides are composed of two cis-fused tetrahydrofuran rings,nearly planar and V-shaped with a 120° angle between rings. The hydroxylgroups are situated at carbons 2 and 5 and positioned on either insideor outside the V-shaped molecule. They are designated, respectively, asendo or exo. Isoidide has two exo hydroxyl groups, while the hydroxylgroups are both endo in isomannide, and one exo and one endo hydroxylgroup in isosorbide. The presence of the exo substituents increases thestability of the cycle to which it is attached. Also exo and endo groupsexhibit different reactivities since they are more or less accessibledepending on the steric requirements of the derivatizing reaction.

As interest in chemicals derived from natural resources is increases,potential industrial applications have generated interest in theproduction and use of isohexides. For instance, in the field ofpolymeric materials, the industrial applications have included use ofthese diols to synthesize or modify polycondensates. Their attractivefeatures as monomers are linked to their rigidity, chirality,non-toxicity, and the fact that they are not derived from petroleum. Forthese reasons, the synthesis of high glass transition temperaturepolymers with good thermo-mechanical resistance and/or with specialoptical properties is possible. Also the innocuous character of themolecules opens the possibility of applications in packaging or medicaldevices. For instance, production of isosorbide at the industrial scalewith a purity satisfying the requirements for polymer synthesis suggeststhat isosorbide can soon emerge in industrial polymer applications. (Seee.g., F. Fenouillot et al., “Polymers From Renewable1,4:3,6-Dianhydrohexitols (Isosorbide, Isommanide and Isoidide): AReview,” PROGRESS IN POLYMER SCIENCE, vol. 35, pp. 578-622 (2010); or X.Feng et al., “Sugar-based Chemicals for Environmentally sustainableApplications,” CONTEMPORARY SCIENCE OF POLYMERIC MATERIALS, Am. Chem.Society, December 2010; or isosorbide-based plasticizers, e.g., U.S.Pat. No. 6,395,810, contents of each are incorporated herein byreference.)

A kind of derivative that can be made is ethers of isohexides.Conventionally, ethers of dianhydrosugars are prepared by contactingalkyl halides and dialkylsulfates with an anhydrosugar, in the presenceof a base or phase transfer catalysts (PTC's, e.g.,tetra-n-butylammonium bromide, benzyltriethyammonium bromide orN-methyl-N,N-dioctyloctan-1-aminium chloride). Notwithstanding theinherent costs of these exotic PTC's, these processes generally needhighly pure anhydrosugar feedstock as a starting material, and sufferfrom both cumbrous and costly downstream separation operations toeffectuate propitious target purities. These issues have complicatedefforts to achieve cost effective yields at significant quantity andquality.

To better take advantage of isohexides as a green feedstock, a clean andsimple method of preparing the isohexides as a platform chemical orprecursor that can be subsequently modified to synthesize othercompounds would be welcome by those in the green or renewable chemicalsindustry. A more cost efficient process is needed as a way to unlock thepotential of anhydrosugars and their derivative compounds, as thesechemical entities have gained attention as valuable antecedents for thepreparation of polymers, solvents, additives, lubricants, andplasticizers, etc. Furthermore, the inherent, immutable chirality ofanhydrosugars makes these compounds useful as potential species forpharmaceutical applications or candidates in the emerging chiralauxiliary field of asymmetric organic synthesis. Given the potentialuses, a cost efficient and simple process that can synthesis derivativesfrom anhydrosugars would be appreciated by manufacturers of bothindustrial and specialty chemicals alike as a way to better utilizebiomass-derived carbon resources.

SUMMARY OF THE INVENTION

The present disclosure describes a method for alkylation of anhydrosugaralcohols (isohexides) using a carbonate reagent. In particular, thealkylation method involves: a) contacting an isohexide with a dialkyl,diallyl, or diaryl carbonate, and a Brønsted base; and b) producing atleast an alkyl ether or alkyl carbonate of the isohexide compound. Thealkylation reaction is in situ, that is, performed without an extrinsiccatalyst. The Brønsted base has a pKa of at least 4, which helpsdeprotonates the isohexide compound. The isohexide is at least one ofthe following: isosorbide, isomannide, and isoidide. The dialkyl,diallyl, or diaryl carbonate has an R-group having 1 to 20 carbon atoms.When the R-group is at least a methyl, ethyl, propyl group, an ether isproduced, and when the R-group is at least a C₄-C₂₀ group, a carbonateis generated. The resultant ether or carbonate, respectively, can beeither: a mono-alkyl ether or dialkyl ether, or mono-alkyl, mono-allyl,mono-aryl carbonate, or dialkyl, diallyl, or diaryl carbonate.

In another aspect, the present disclosure pertains to certain ethers andcarbonates synthesized according the foregoing method. In general, thealkylated ether of the isohexide compound is at least one of thefollowing: mono-ether of isoidide; mono-ether of isomannide; mono-etherof isosorbide; di-ether of isoidide; di-ether of isomannide; anddi-ether of isosorbide, wherein the resultant ether has at least one ofthe following alkyl groups: a mono-methyl, mono-ethyl, mono-propyl,di-methyl, di-ethyl, or di-propyl. Generally, the alkylated carbonate ofthe isohexide compound is at least one of the following: mono-carbonateof isoidide; mono-carbonate of isomannide; mono-carbonate of isosorbide;di-carbonate of isoidide; di-carbonate of isomannide; and di-carbonateof isosorbide, wherein the resultant carbonate has at least one of thefollowing alkyl, allyl or aryl groups: a mono-butyl, mono-pentyl,mono-hexyl, mono-benzyl, mono-phenyl, mono-allyl, di-butyl, di-pentyl,dihexyl, di-benzyl, di-phenyl, di-allyl, or a mono- or di-alkyl groupfrom C₇-C₂₀ carbon atoms.

Additional features and advantages of the present process will bedisclosed in the following detailed description. It is understood thatboth the foregoing summary and the following detailed description andexamples are merely representative of the invention, and are intended toprovide an overview for understanding the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION Section I Description

As biomass derived compounds that afford great potential as surrogatesfor non-renewable petrochemicals, 1,4:3,6-dianhydrohexitols are a classof bicyclic furanodiols that are valued as renewable molecular entities.(For sake of convenience, 1,4:3,6-dianhydrohexitols will be referred toas “isohexides” in the Description hereinafter.) As referred to above,the isohexides are good chemical platforms that have recently receivedinterest because of their intrinsic chiral bi-functionalities, which canpermit a significant expansion of both existing and new derivativecompounds that can be synthesized.

Isohexide starting materials can be obtained by known methods of makingrespectively isosorbide, isomannide, or isoidide. Isosorbide andisomannide can be derived from the dehydration of the correspondingsugar alcohols, D-sorbitol and D mannitol respectively. As a commercialproduct, isosorbide is also available easily from a manufacturer. Thethird isomer, isoidide, can be produced from L-idose, which rarelyexists in nature and cannot be extracted from vegetal biomass. For thisreason, researchers have been actively exploring different synthesismethodologies for isoidide. For example, the isoidide starting materialcan be prepared by epimerization from isosorbide. In L. W. Wright, J. D.Brandner, J. Org. Chem., 1964, 29 (10), pp. 2979-2982, epimerization isinduced by means of Ni catalysis, using nickel supported on diatomaceousearth. The reaction is conducted under relatively severe conditions,such as a temperature of 220° C. to 240° C. at a pressure of 150atmospheres. The reaction reaches a steady state after about two hours,with an equilibrium mixture containing isoidide (57-60%), isosorbide(30-36%) and isomannide (5-7-8%). Comparable results were obtained whenstarting from isoidide or isomannide. Increasing the pH to 10-11 wasfound to have an accelerating effect, as well as increasing thetemperature and nickel catalyst concentration. A similar disclosure canbe found in U.S. Pat. No. 3,023,223, which proposes to isomerizeisosorbide or isomannide. More recently, P. Fuertes proposed a methodfor obtaining L-iditol (precursor for isoidide), by chromatographicfractionation of mixtures of L-iditol and L-sorbose (U.S. PatentPublication No. 2006/0096588; U.S. Pat. No. 7,674,381 B2). L-iditol isprepared starting from sorbitol. In a first step sorbitol is convertedby fermentation into L-sorbose, which is subsequently hydrogenated intoa mixture of D-sorbitol and L-iditol. This mixture is then convertedinto a mixture of L-iditol and L-sorbose. After separation from theL-sorbose, the L-iditol can be converted into isoidide. Thus, sorbitolis converted into isoidide in a four-step reaction, in a yield of about50%. (The contents of the cited references are incorporated herein byreference.)

These molecular entities hold significant potential as “green”,renewable solvents derived from biomass, as well as platform chemicals(monomethyl ethers) for the production of surfactants, dispersants, andemollients (personal care products). Furthermore, the reagents used inthe aforementioned preparation are non-toxic, environmentally friendlysubstances.

A

In the present disclosure, benign, environmentally friendly carbonate(e.g., diethyl carbonate or potassium carbonate) are employed tosynthesize ethers and carbonates. Schemes 1 and 2 are generalizedillustrations of embodiments of the present synthesis process. Scheme 1depicts an embodiment in which an isohexide is reacted with a carbonatehaving C₁-C₃ alkyl R-groups using a Brønsted base to generate acorresponding ether. Scheme 2 shows an alternate embodiment in which anisohexide is reacted with a carbonate having C₄ and greater alkyl,phenyl, allyl R-groups using a Brønsted base to produce a correspondingcarbonate. The base serves to deprotontate the isohexide intermediate togenerate the ether or carbonate compounds. The base should be reasonablysoluble in solution to afford satisfactory mixing and subsequentreactivity.

Preferably, the reaction time for each synthesis can be within about 24hours. Typically, the reaction time is within about 6 hours to about 12hours (e.g., 7 or 8 hours to about 9 or 10 hours). As the reactionproceeds for longer durations (e.g., ˜10-24 hours) the yieldsrespectively of mono-ether and di-ether products will increase to fullconversion of the di-ether species. For the carbonate products, themono-carbonate species quickly converts to the di-carbonate specieswithin about 1-2 hours.

The Brønsted base should have a minimal pKa of about 4 (e.g., pyridine).Typically, the base pKa is about 7-14, usually about 8 or 10 to about 12or 13. In alternative embodiments, some bases may have a greater pKa, upto about 40-55 (e.g., alkyl-lithium). Various kinds of Brønsted basescan be used, for example, the base can be one of the following: acarbonate (e.g., sodium or potassium carbonate); a hindered amine (e.g.,triethylamine, tributylamine, diisopropylethylamine (DIEA),dibutylamine); a nucleophilic base (e.g., pyridine, pyrimidine,dimethyl-aminopyridine, imidazole, pyrrolidine, morpholine); a sodium,potassium, or calcium hydride; or an organometallic compound (e.g.,alkyl-lithium or alkyl-magnesium). The minimum stoichiometricequivalents of base to the staring materials is about 1 for mono-etheror mono-carbonate, and about 2 equivalents depending on the solubilityof the carbonate or miscibility of the base (e.g., amines) in solution.

Using a non-nucleophilic amine that is sterically hindered, such asdiisopropylethylamine (DIEA), can enhance the process not only from itssolubilizing capacity and basicity, but ease of sequestration via mildaqueous acid treatment.

The Brønsted base in some embodiments is a solid compound, such as amineral carbonate, which would make the removal and purification of thefinal product from solution easier. In other embodiments, hinderedamines, owing to their innate liquidity and ease of segregation by mildacid treatment comprise other salutary bases for this process. Theliquid hindered amine allows for better mixing and miscibility butremoval is more complex involving a titration with acid and thenliquid-liquid extraction.

For instance, isosorbide diallyldicarbonate separates in the form ofviscous oil, and can be stored indefinitely, with negligibledegradation, in an inert atmosphere.

According to the present invention, the alkylation reaction can beconducted at a temperature in a range from about 70° C. or 80° C. toabout 180° C. or 200° C., inclusive, depending on the boiling pointtemperature of the particular carbonate solvent used in the reaction(e.g., 75° C. for dimethyl carbonate, or 120° C. for diethyl carbonate).Typically, the reaction temperature is in a range from about 85° C. or90° C. or 100° C. to about 160° C., 170° C. or 175° C., inclusive ofvarious combinations of ranges therein. As a general consideration, thelonger or greater the number of carbons in an alkyl, allyl or arylgroup, respectively, of the dialkyl, diallyl, or diaryl carbonatereagent, the higher the boiling point tends to be; hence, the greaterthe reaction temperature. As a precaution, one risks decarboxylation ofthe carbonate even though one may achieve greater conversion of theisohexide to its corresponding ether or carbonate at significantlyhigher temperatures. Particular temperature ranges for example may befrom about 110° C. or 120° C. to about 140° C. or 150° C., inclusive ofcombination of ranges therein. In certain desirable iterations, thereaction is performed at a temperature between about 115° C., 117° C. or120° C. to about 125° C., or 130° C., or 135° C.

To prepare monoethers, the reaction should use at least 1 to 2equivalents of carbonate for each equivalent of isohexide consumed. Fordiethers, at least 2 equivalents are used.

We observe that carbonates with R-groups having C₁-C₃ carbons tend togenerate ethers, while those with C₄-C₆ make predominately carbonates,and those with C₇-C₂₀ make only carbonates. It is believed that thepossible steric interference from longer chain alkyl, allyl, or arylgroups tends to favor the formation of the carbonate species over theether species.

Typically as a solvent, one may include an alcohol having the sameR-species as that which is displaced from the carbonate molecule, suchas, an ethanol when reacting with diethylcarbonate, or an allyl alcoholwhen using diallylcarbonate, such in Scheme 3. It is believed that insurplus alcohol the carbonate is activated.

In situ transesterification of the incumbent carbonate with excessalcoholic solvent occurs readily, auspiciously permitting alkyletherification to occur without the need for use of carbonates otherthan inexpensive dimethylcarbonate. This is shown in Scheme 4.

The reactions can be executed in a neat solution of dimethyl orethylcarbonate, or as previously detailed, can be generated in situ viatransesterification. The isohexide compound and the dialkyl, diallyl, ordiaryl carbonate are reacted respectively in a neat solution of at leastthe dialkyl, diallyl, or diaryl carbonate. As a cost efficient feature,one can recycle the unconsumed dicarbonate and solvent.

Given the difference in boiling points of the carbonate (˜95° C.) andamine (˜120° C.), the present etherification reactions can simplify andmake the purification and recovery process relatively easy. One candistill both the carbonate and the amine and recycle recovered carbonateafter each reaction.

An illustration of an advantage of the present synthesis process is theemployment of relatively mild conditions and safe non-toxic reagents is,for example, the preparation of(3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl diphenyl dicarbonate,isosorbide diphenylcarbonate, as discussed in Example 4, below. Incontrast, the conventionally way of preparing the same compound caninvolve several reaction steps, and uses harsh conditions and somereagents such as diphosgene or triphosgene, which are toxic (see, e.g.,Noordover, Bart A. J., et al., “Chemistry, Functionality, and CoatingPerformance of Biobased Copolycarbonates from1,4:3,6-Dianhydrohexitols,” J. APPLIED POLYMER SCIENCE, Vol. 121,1450-1463 (2011); Sun, S. J., et al., “New polymers of carbonic acid.XXV. Photoreactive cholesteric polycarbonates derived from2,5-bis(4′-hydroxybenzylidene)cyclopentanone and isosorbide” J. POLYMERSCIENCE: PART A: POLYM. CHEM., Vol. 37, 1125-1133 (1999); Kricheldorf,H. R., et al., “Polymers of Carbonic Acid,” MACROMOLECULES, Vol. 29,8077-8082 (1996)).

B

Several plausible variations to the present synthesis methodology can beapplied to generate high yields of monoethyl or diethyl targets. Theseadjustments may include, though are not restricted to:

1) organic bases: all linear and cyclic amines, such as triethylamine,Hunig's base, DBU, and piperidine;

2) inorganic bases: alkali and alkali earth metal carbonates, such ascesium carbonate, calcium carbonate;

3) basic resins: for continuous processes, resins with basic-cappedfunctionalities;

4) other alkyl carbonates: transesterification of carbonates that can beimplimented with relatively inexpensive dimethyl or diethyl carbonatesin an excess alcohol and with a Lewis acid catalyst. For example,isoidide mono and dibenzylethers can be generated from the in situproduction of dibenzyl carbonate (dimethyl carbonate, a surfeit ofbenzyl alcohol, and catalyst) using the present method.

The alkylated isohexide compound prepared by the present method iseither an ether or a carbonate. The isohexide ether can be at least oneof the following: a mono-alkyl ether or dialkyl ether. The ethercompound can be, for example: an isoidide monoethylether, with astructure:

or an isoidide diethylether, with a structure:

In other embodiments, the alkylated isohexide ether can be one of thefollowing: mono-methyl ether of isoiodide; mono-ethyl ethers, ofisosorbide, isommanide, or isoiodide, respectively; diethyl ester ofisoiodide; mono-propyl ether of isomannide; dipropyl ether ofisomannide; mono-propyl ether of isoidide; dipropyl ether of isoiodide;mono-benzyl ether of isoidide; monoallyl ethers of isosorbide,isommanide, or isoiodide, respectively; and diallyl ethers ofisosorbide, isommanide, or isoiodide, respectively.

Isoidide monoethylether (IUPAC:(3S,3aR,6S,6aR)-6-ethoxyhexahydrofuro[3,2-b]furan-3-ol) and isoididediethylether (IUPAC:(3S,3aR,6S,6aR)-6-ethoxyhexahydrofuro[3,2-b]furan-3-ol). Examples of thediethyl ethers of isomannide and isosorbide, as well as thecorresponding monoethyl ethers can be formed in high yields. It isbelieved that the monomethyl ethers of isomannide and isosorbide are newcompositions of matter.

When a carbonate is made according to the present method, the carbonatecompound can be at least one of the following: a mono-alkyl carbonate,dialkyl carbonate, mono- or di-aryl carbonate, mono- or di-allylcarbonate, or a carbonate with an alkyl group from 4-20 carbon atoms. Inan example, the carbonate compound is: isosorbide diallyldicarbonate,with a structure:

In other embodiments, the isohexide carbonate can be one of thefollowing: mono-methylcarbonate of isomannide; mono-methylcarbonate ofisoidide; dimethylcarbonate of isomannide; dimethylcarbonate ofisoidide; monoethylcarbonates of isosorbide, isommanide, or isoiodide,respectively; diethylcarbonate of isomannide; diethylcarbonate ofisoidide; mono-propyl or dipropylcarbonates of isosorbide, isommanide,or isoiodide, respectively; mono- or dicarbonates having an alkylR-group of C₄ to C₂₀ of isosorbide, isommanide, or isoiodide,respectively; mono-benzyl or dibenzyl carbonates of isosorbide,isommanide, or isoiodide, respectively; monophenylcarbonates ofisosorbide, isommanide, or isoiodide, respectively; anddiphenylcarbonates of isomannide or isoidide, respectively.

Particular illustrative examples of derivative compounds that can bemade from both FDM and THF-sulfonates are presented in the associatedexamples that follow.

Section II Examples

The following examples are provided as illustration of the differentaspects of the present disclosure, with the recognition that alteringparameters and conditions, for example by change of temperature, timeand reagent amounts, and particular starting species and catalysts andamounts thereof, can affect and extend the full practice of theinvention beyond the limits of the examples presented.

Example 1 Ethyl Etherification of Isoidide with Diethyl Carbonate andPotassium Carbonate

Experimental:

A 100 mL boiling flask equipped with a PTFE coated magnetic stir bar wascharged with 2 grams of isoidide (13.7 mmol), 9.45 grams of potassiumcarbonate (68.4 mmol), and 50 mL of diethyl carbonate (413 mmol). Whilestirring, the heterogeneous mixture was heated to 120° C. for 8 hours.After this time, the residual potassium carbonate was removed byfiltration, the filtrate stored. Three spots were identified on TLC (98%EtOAc/2% MeOH, cerium molybdate stain), Rf₁=0.76, Rf₂=0.44, Rf₃=0.24(isoidide). A sample was analyzed, qualitatively, by GC/MS that revealeda very small amount of residual isoidide, with two preponderant signalsthat were congruous with the mono and diethyl analogs of isoidide. Asample was then submitted for quantitative analysis, which produced thefollowing mass ratios: Isoidide—12.5%; isoidide monoethyl ether—50.9%;isoidide diethyl ether—33.7%.

Comparative Example 1 Failed Etherification of Isoidide with DiethylCarbonate, Potassium Carbonate, and Ethanol

A 100 mL boiling flask was charged with 2 grams of isoidide (13.7 mmol),9.45 grams of potassium carbonate (68.4 mmol), 8.30 mL of diethylcarbonate (68.4 mmol) and 50 mL of ethanol. The heterogeneous mixturewas heated to reflux (˜85° C. for 24 hours. Samples of the reactionmixture were removed at 2 hour increments and analyzed by GC/MS. After24 h, no mono or di-methyl ethers of isoidide were descried.

It is interesting that isoidide methyl etherification was quantitativewith dimethylcarbonate in methanol but completely failed with diethylcarbonate in ethanol. An explicit rationalization cannot be derived atthis time, but could involve either 1) steric effects of the ethyl chainand/or 2) solubility of potassium carbonate in ethanol.

Example 2 Ethyl Etherification of Isosorbide with Diethyl Carbonate andPotassium Carbonate

Experimental:

A 100 mL boiling flask equipped with a PTFE coated magnetic stir bar wascharged with 2 grams of isosorbide (13.7 mmol), 9.45 grams of potassiumcarbonate (68.4 mmol), and 50 mL of diethyl carbonate (413 mmol). Whilestirring, the heterogeneous mixture was heated to 120° C. for 8 hours.After this time, the residual potassium carbonate was removed byfiltration, the filtrate stored. Four spots were identified on TLC (98%EtOAc/2% MeOH, cerium molybdate stain), Rf₁=0.76, Rf₂=0.44, Rf₃=0.42 andRf₄=0.20 (isosorbide). A sample was analyzed, qualitatively, by GC/MSthat revealed a very small amount of residual isosorbide, with threeprimary signals that were consistent with the mono and diethyl analogsof isoidide. A sample was then submitted for quantitative analysis,which produced the following mass ratios: Isosorbide—15.2%; isosorbidemonoethyl ethers—55.2%; isosorbide diethyl ether—26.7%.

Example 3 Ethyl Etherification of Isomannide with Diethyl Carbonate andPotassium Carbonate

Experimental:

A 100 mL boiling flask equipped with a PTFE coated magnetic stir bar wascharged with 2 grams of isomannide (13.7 mmol), 9.45 grams of potassiumcarbonate (68.4 mmol), and 50 mL of diethyl carbonate (413 mmol). Whilestirring, the heterogeneous mixture was heated to 120° C. for 8 hours.After this time, the residual potassium carbonate was removed byfiltration, the filtrate stored. Three spots were identified on TLC (98%EtOAc/2% MeOH, cerium molybdate stain), Rf₁=0.78, Rf₂=0.39, and Rf₃=0.18(isomannide). A sample was analyzed, qualitatively, by GC/MS thatrevealed a very small amount of residual isomannide, with two primarysignals that were consistent with the mono and diethyl analogs ofisomannide. A sample was then submitted for quantitative analysis, whichproduced the following mass ratios: Isomannide—13.1%; isosorbidemonoethyl ethers—49.4%; isosorbide diethyl ether—30.5%.

Example 4 Synthesis of(3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl diphenyl dicarbonate,Isosorbide Diphenylcarbonate, D

Experimental:

A 25 mL round bottomed flask equipped with an oval PTFE coated magneticstir bar was charged with 1 g of isosorbide A (6.84 mmol), 3.78 g ofpotassium carbonate (27.36 mmol) and 10 g of diphenylcarbonate B (46.7mmol). While stirring, the heterogeneous mixture was heated to 140° C.overnight (a profusion of effervescence was noted). At this time thereaction was deemed complete by TLC (1% methanol in ethyl acetate,UV-Vis and cerium molybdate illumination) as signified by the absence ofisosorbide and presence of only 2 spots. The heterogeneous mixture wasdiluted with ethanol and filtered to remove excess salts. A white solidappeared in the filtrate during the sequestration, which was filtered,dried, and analyzed by ¹H NMR, indicating isosorbide diphenylcarbonate D(1.55 g, 59%). No isosorbide diphenylether C was descried by thisanalytical technique in the mother liquor. ¹H NMR (CDCl₃, 400 MHz) δ(ppm) 7.41-7.40 (m, 4H), 7.39-7.38 (m, 4H), 7.22-7.20 (m, 2H), 5.24-5.21(m, 1H), 5.03 (d, J=5.6 Hz, 1H), 4.67 (t, J=9.8 Hz, 1H), 4.33 (d, J=8.2Hz, 1H), 4.26 (d, J=10.4 Hz, 1H), 4.23-4.22 (dd, J=9.8 Hz, J=1.4 Hz,1H), 4.15-4.14 (dd, J=9.6 Hz, J=3.2 Hz, 1H), 4.02-4.01 (dd, J=9.2 Hz,J=2.6 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm) 153.32, 153.01, 151.26,151.10, 129.88, 129.81, 121.31, 115.55, 86.04, 82.00, 81.31, 76.94,73.44, 70.90.

Example 5 Synthesis of(3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl diphenyl dicarbonate,C

Experimental:

A 25 mL round bottomed flask equipped with an oval PTFE coated magneticstir bar was charged with 1 g of isoidide A (6.84 mmol), 3.78 g ofpotassium carbonate (27.36 mmol) and 10 g of diphenylcarbonate B (46.7mmol). While stirring, the heterogeneous mixture was heated at 140° C.overnight (significant bubbling was observed). After this time thereaction was deemed complete by TLC (1% methanol in ethyl acetate,UV-Vis and cerium molybdate illumination) as signified by the absence ofisoidide and presence of only 2 spots. The heterogeneous mixture wasdiluted with ethanol and filtered to remove excess salts. A white solidappeared in the filtrate during the sequestration, which was filtered,dried, and analyzed by ¹H NMR, indicating isoidide diphenylcarbonate D(1.76 g, 66%). ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 7.36-7.34 (m, 4H),7.31-7.28 (m, 4H), 7.21-7.19 (m, 2H), 4.97-4.95 (m, 2H), 4.82 (d, J=5.5Hz, 4H), 4.37 (m, 2H), 4.32 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm)153.67, 151.04, 129.92, 129.87, 122.07, 116.38, 89.52, 84.84, 70.48.

Example 6 Synthesis of(3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl diphenyl dicarbonate,C

Experimental:

A 25 mL round bottomed flask equipped with an oval PTFE coated magneticstir bar was charged with 1 g of isomannide A (6.84 mmol), 3.78 g ofpotassium carbonate (27.36 mmol) and 10 g of diphenylcarbonate B (46.7mmol). While stirring, the heterogeneous mixture was heated at 140° C.overnight (significant bubbling was observed). After this time thereaction was deemed complete by TLC (1% methanol in ethyl acetate,UV-Vis and cerium molybdate illumination) as signified by the absence ofisomannide and presence of only 2 spots. The heterogeneous mixture wasdiluted with ethanol and filtered to remove excess salts. A white solidappeared in the filtrate during the sequestration, which was filtered,dried, and analyzed by ¹H NMR, indicating isoidide diphenylcarbonate D(1.31 g, 49%). ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 7.41-7.40 (m, 4H),7.39-7.38 (m, 4H), 7.22-7.20 (m, 2H), 5.12-5.09 (m, 2H), 4.97 (d, J=5.8Hz, 4H), 4.51 (m, 2H), 4.42 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm)153.44, 150.94, 129.81, 129.77, 122.00, 116.03, 91.37, 86.38, 70.23.

Example 7 Synthesis of diallyl((3R, 3aR, 6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl)dicarbonate, isosorbidediallyldicarbonate

Experimental:

An oven dried, 25 mL round bottomed flask equipped with a PTFE coatedmagnetic stir bar was charged with 100 mg of isosorbide (A, 0.684 mmol),1 mL of diallylcarbonate (7.03 mmol), and 477 μL ofdiisopropylethylamine (DIEA, 2.74 mmol). A reflux condenser capped withan argon inlet was affixed to the round bottomed flask and the mixtureheated to 120° C. overnight with vigorous stirring. After this time, analiquot was removed, diluted with acetone and analyzed by GC/MS. Thecharacteristic signal for isosorbide was absent, indicating fullconversion. No other signals were manifest, precluding the presence ofdiallyisosorbide, C or monoallylisosorbide isomers. The absence of thediallyl analog was corroborated by TLC (1:1 EtOAc:Hexanes, ceriummolybdate stain), where an authentic sample of diallylisosorbide wasloaded adjacent to the product mixture. The signature spot was notobserved in the product mixture. Product workup entailed dilution withacetone, filtration to remove orange solids, and concentration in vacuo,resulting in an oil with a light-yellow color (162 mg, 75.0%). ¹H NMRanalysis (CDCl₃, 400 MHz) δ (ppm) 5.97-5.91 (m, 2H), 5.39-5.38 (dd,J=13.2 Hz, J=1.2 Hz, 1H), 5.35-5.34 (dd, J=13.2 Hz, J=1.3 Hz, 1H),5.30-5.29 (dd, J=8.6 Hz, J=1.0 Hz, 1H), 5.27-5.26 (dd, J=8.4 Hz, J=1.2Hz, 1H), 5.11-5.09 (m, 2H), 4.90 (t, J=5.2 Hz, 1H), 4.67 (d, J=6.4 Hz,2H), 4.64 (d, J=6.2 Hz), 4.57 (d, J=6.6 Hz, 1H), 4.07-4.03, (m, 2H),3.91-3.90 (m, 2H). ¹³C NMR (CDCl₃, 125 MHz) δ (ppm) 154.56, 154.21,131.48, 131.34, 119.62, 119.28, 86.07, 81.43, 81.10, 73.46, 70.70,69.07, 69.04, 68.89.

Example 8 Synthesis of diallyl((3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl) dicarbonate, B

Experimental:

An oven dried, 25 mL round bottomed flask equipped with a PTFE coatedmagnetic stir bar was charged with 100 mg of isoidide (A, 0.684 mmol), 1mL of diallylcarbonate (7.03 mmol), and 477 μL of diisopropylethylamine(DIEA, 2.74 mmol). A reflux condenser capped with an argon inlet wasaffixed to the round bottomed flask and the mixture heated to 120° C.overnight while vigorously stirring. After this time, an aliquot wasremoved, diluted with acetone and analyzed by GC/MS. The characteristicsignal for isoidide was absent, indicating full conversion. Productworkup entailed dilution with acetone, filtration to remove brownsolids, and concentration in vacuo, resulting in an oil with alight-yellow color (144 mg, 66.9%). ¹H NMR analysis (CDCl₃, 400 MHz) δ(ppm) 5.97-5.91 (m, 2H), 5.49-5.46 (m, 2H), 5.35-5.34 (m, 2H), 4.97-4.95(m, 2H), 4.80 (d, J=5.5 Hz, 4H), 4.65 (d, J=7.2 Hz, 4H), 4.35 (m, 2H),4.29 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm) 153.33, 131.28, 117.74,90.34, 81.63, 70.07, 62.51.

Example 9 Synthesis of diallyl((3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl) dicarbonate, B

Experimental:

An oven dried, 25 mL round bottomed flask equipped with a PTFE coatedmagnetic stir bar was charged with 100 mg of isomannide (A, 0.684 mmol),1 mL of diallylcarbonate (7.03 mmol), and 477 μL ofdiisopropylethylamine (DIEA, 2.74 mmol). A reflux condenser capped withan argon inlet was affixed to the round bottomed flask and the mixtureheated to 120° C. overnight with vigorous stirring. After this time, analiquot was removed, diluted with acetone and analyzed by GC/MS. Thecharacteristic signal for isomannide was absent, indicating fullconversion. Product workup entailed dilution with acetone, filtration toremove brown solids, and concentration in vacuo, resulting in an oilwith a light-yellow color (145 mg, 67.3%). ¹H NMR analysis (CDCl₃, 400MHz) δ (ppm) 5.95-5.90 (m, 2H), 5.46-5.44 (m, 2H), 5.33-5.31 (m, 2H),5.11-5.08 (m, 2H), 4.96 (d, J=5.8 Hz, 4H), 4.61 (d, J=7.2 Hz, 4H), 4.53(m, 2H), 4.40 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ (ppm) 153.72, 131.94,117.38, 91.66, 82.07, 69.41, 60.99.

The present invention has been described in general and in detail by wayof examples. Persons of skill in the art understand that the inventionis not limited necessarily to the embodiments specifically disclosed,but that modifications and variations may be made without departing fromthe scope of the invention as defined by the following claims or theirequivalents, including other equivalent components presently know or tobe developed, which may be used within the scope of the invention.Therefore, unless changes otherwise depart from the scope of theinvention, the changes should be construed as being included herein.

We claim:
 1. A method of alkylating an anhydrosugar compound comprising:a) contacting an isohexide compound with a dialkyl, diallyl, or diarylcarbonate and a Brønsted base; and b) producing at least an alkyl etheror alkyl carbonate of the isohexide compound.
 2. The method according toclaim 1, wherein the anhydrosugar compound is at least one of:isosorbide, isomannide, and isoidide.
 3. The method according to claim1, wherein said dialkyl, diallyl, or diaryl carbonate has an R-grouphaving 1 to 20 carbon atoms.
 4. The method according to claim 3, whereinwhen said R-group is at least one of methyl, ethyl, propyl group, saidalkyl ether is produced predominantly.
 5. The method according to claim3, wherein when said R-group is at least a C₄-C₂₀ group, said alkylcarbonate is produced predominantly.
 6. The method according to claim 1,wherein said alkylated ether of said isohexide compound is at least oneof: mono-ether of isoidide, mono-ether of isomannide, mono-ether ofisosorbide, di-ether of isoidide, di-ether of isomannide, and di-etherof isosorbide.
 7. The method according to claim 3, wherein saidalkylated isohexide compound is an ether having at least one of thefollowing alkyl groups: a mono-methyl, mono-ethyl, mono-propyl,di-methyl, di-ethyl, or di-propyl isohexide ether.
 8. The methodaccording to claim 1, wherein said alkylated carbonate of said isohexidecompound is at least one of: mono-carbonate of isoidide; mono-carbonateof isomannide; mono-carbonate of isosorbide; di-carbonate of isoidide;di-carbonate of isomannide; and di-carbonate of isosorbide.
 9. Themethod according to claim 5, wherein said alkylated isohexide compoundis a carbonate having at least one of the following alkyl, allyl or arylgroups: a mono-butyl, mono-pentyl, mono-hexyl, mono-benzyl, mono-phenyl,mono-allyl, di-butyl, di-pentyl, dihexyl, di-benzyl, di-phenyl,di-allyl, or a mono- or di-alkyl group from C₇-C₂₀ carbon atoms.
 10. Themethod according to claim 1, wherein said anhydrosugar compound and saiddialkyl, diallyl, or diaryl carbonate are contacted at a temperature ina range from about 70° C. to about 200° C.
 11. The method according toclaim 10, wherein said anhydrosugar compound and said dialkyl, diallyl,or diaryl carbonate are contacted at a temperature in arrange from about80° C. to about 150° C.
 12. The method according to claim 1, whereinsaid anhydrosugar compound and said dialkyl, diallyl, or diarylcarbonate are contacted in a neat solution of said dialkyl, diallyl, ordiaryl carbonate.
 13. The method according to claim 1, wherein saidBrønsted base has a pKa of at least
 4. 14. The method according to claim13, wherein said Brønsted base has a pKa 7-14.
 15. The method accordingto claim 1, wherein said Brønsted base is at least one of the following:a carbonate; a hindered amine; a nucleophilic base; a sodium, potassiumor calcium hydride; or an organometallic compound.
 16. The methodaccording to claim 15, wherein said organometallic compound is analkyl-lithium or alkyl-magnesium.
 17. An ether compound preparedaccording to the method of claim 1, wherein said ether compound is atleast one of the following: a monoalkyl ether or dialkyl ether.
 18. Theether compound according to claim 17, wherein said ether compound has astructure:

wherein for a dialkyl ether, R is a C₁-C₃ alkyl group; and, for amonoalkyl ether, one R is a C₁-C₃ alkyl group and another is an OH. 19.The ether compound according to claim 17, wherein said ether compound isat least: an isoidide monoethylether, with a structure:

an isoidide diethylether, with a structure:


20. The alkylated isohexide compound according to claim 17, wherein saidcompound is an ether selected from the group consisting of: mono-methylether of isoiodide; mono-ethyl ethers, of isosorbide, isommanide, orisoiodide, respectively; diethyl ester of isoiodide; mono-propyl etherof isomannide; dipropyl ether of isomannide; mono-propyl ether ofisoidide; dipropyl ether of isoiodide; mono-benzyl ether of isoidide;monoallyl ethers of isosorbide, isommanide, or isoiodide, respectively;and diallyl ethers of isosorbide, isommanide, or isoiodide,respectively.
 21. A carbonate compound prepared according to the methodof claim 1, wherein said carbonate compound is at least one of thefollowing: a mono-alkyl carbonate, dialkyl carbonate, mono- or di-arylcarbonate, mono- or di-allyl carbonate, or a carbonate with an alkylgroup from 4-20 carbon atoms.
 22. The carbonate compound according toclaim 21, wherein said carbonate compound has a structure:

wherein for a dialkyl carbonate, R is a C₄ or higher carbon alkyl,phenyl, allyl group; and, for a monoalkyl ether, one R is a C₄ or highercarbon alkyl, phenyl, allyl group and another is an OH.
 23. Thecarbonate compound according to claim 21, wherein said carbonatecompound is: isosorbide diallyldicarbonate, with a structure:


24. The alkylated isohexide compound according to claim 21, wherein saidcompound is a carbonate selected from the group consisting of:mono-methylcarbonate of isomannide; mono-methylcarbonate of isoidide;dimethylcarbonate of isomannide; dimethylcarbonate of isoidide;monoethylcarbonates of isosorbide, isommanide, or isoiodide;diethylcarbonate of isomannide; diethylcarbonate of isoidide;mono-propyl or dipropylcarbonates of isosorbide, isommanide, orisoiodide; mono- or dicarbonates having an alkyl R-group of C₄ to C₂₀ ofisosorbide, isommanide, or isoiodide, respectively; mono-benzyl ordibenzyl carbonates of isosorbide, isommanide, or isoiodide,respectively; monophenylcarbonates of isosorbide, isommanide, orisoiodide, respectively; and diphenylcarbonates of isomannide orisoidide.